Among the most common causes of death in the United States, septic shock (SS) is reported to be the first in non-coronary intensive care units. Physicians have noted that physiologic alternations and organ dysfunction which are commonly seen with bacterial infections, and which may result in SS, could also result from a wide variety of clinical insults which do not originate from any one specific bacterial infection. This clinical state, termed the Systemic Inflammatory Response Syndrome (SIRS) was generally defined by two or more changes in the following four-factors: body temperature, heart rate, respiratory function and peripheral leukocyte count.
SIRS may affect all organ systems and may lead to multiple organ dysfunction syndromes. The hallmark of SIRS is the creation of a proinflammatory state that is marked by tachycardia, tachypnea or hyperpnea, hypotension, hypoperfusion, oliguria, leukocytosis or leucopenia, pyrexia or hypothermia and the need for volume infusion. This condition characteristically does not include a documented source of infection. Metabolic acidosis is a frequent accompaniment to SIRS and it is derived principally from lactate.
The trigger of SIRS is unclear. Advanced competing theories such as second-hit hypothesis, intestine as the motor of SIRS, chaos theory and immunologic inflammation have been suggested as possible theories and mechanism involved in explaining the evolution and/or appearance of SIRS. A few important cell-to-cell signaling molecules have been variably implicated in the genesis of the proinflammatory state. These messengers include among others interleukin IL-1, IL-5, IL-6, IL-8, IL-11, IL-15 and multiple colony stimulating factors, as well as the chemokines.
Similar findings have been made for tumor necrosis factor (TNF)-α and other related molecules that arise from infectious agents such as lipopolysaccharide, staphylococcal enterotoxins A-E and toxic shock syndrome toxin.
TNF-α and β have been extensively studied and have exhibited their role in host defenses against infection and other disease states. The biological effects of the TNFs are mediated through the two membrane associated receptors, TNFR1 (p55) and TNFR2 (p75) that are expressed on the target cells. The postulated pathogenic roles for TNF include sepsis and bacterial and viral pathologies, certain cancers, metastasis and chronic autoimmune disorders such as rheumatoid arthritis, multiple sclerosis and Crohn's disease. The levels of TNF-α was increased in patients with chronic heart failure. TNF-α is an important element in ischemic-reperfusion injury after myocardial revascularization.
To date, the two strategies for inhibiting TNF that have been most extensively studied consist of monoclonal anti-TNF antibodies and soluble TNF receptors (sTNF-R). Both constructs theoretically bind to circulating TNF-α, thereby limiting its ability to engage cell membrane-bound TNF receptors and activate inflammatory pathways.
The best studied of the monoclonal anti-TNF antibodies is infliximab (Remicade®), originally referred to as cA2. Infliximab is a chimeric human/mouse monoclonal anti-TNF-α antibody composed of the constant regions of human (Hu) IgG1┐, coupled to the Fv region of a high-affinity neutralizing murine anti-HuTNFa antibody. Because of the potential for an immune reaction to the mouse protein components of a chimeric antibody, an alternate strategy has been to develop a fully human anti-TNF monoclonal antibody. One such antibody, known as D2E7, also known as adalumimab, was generated by phage display technology. A high affinity murine anti-TNF monoclonal antibody was used as a template for guided selection, which involves complete replacement of the murine heavy and light chains with human counterparts and subsequent optimization of the antigen-binding affinity.
In the second approach to TNF inhibition, soluble TNF-R have been engineered as fusion proteins in which the extracellular ligand-binding portion of the huTNF-RI or huTNF-RII was coupled to a human immunoglobulin-like molecule. Although TNF-RI is thought to mediate most of the biological effects of TNF in vivo, engineered sTNF-RI and sTNF-RII constructs both appear to be effective in vivo inhibitors of TNF. Etanercept (sTNF-RII:Fc; Enbrel®) is the best studied of the sTNF-R and is approved for the treatment of rheumatoid arthritis in adults and in children. It is a dimeric construct in which two sTNF-RII (p75) are linked to the Fc portion of human IgG1. The dimeric receptor has a significantly higher affinity for TNF-α than the monomeric receptor (50-1000-fold higher), and the linkage to the Fc structure significantly prolongs the half-life of the construct in vivo. Although it also has an unnatural linkage site, anti-etanercept antibodies have been infrequent. Another mechanism for prolonging the half-life of monomeric receptors is via conjugation with polyethylene glycol.
Animal venom is one of the most amazing and unique adaptations of animal evolution. Venom is a complex mixture of enzymes which prime purpose is to paralyse and digest prey. Substances which are neurotoxic, hemotoxic and proteolytic have been isolated from snake venoms and have been shown to have a somewhat surprising applicability to prophylactic medicine. For example, PCT application WO 01/47535 to Ortenheim et al discloses an antimicrobial composition which comprises at least one snake venom for the prevention, management or treatment of bacterial, fungal, protozoan or viral diseases.
Abbreviations
GOT—glutamic-oxaloacetic transaminase; GPT—glutamic-pyruvic transaminase; IL—interleukin; LDH—lactate dehydrogenase; LPS—lipopolysaccharide; SIRS—systemic inflammatory response syndrome; SS—septic shock; TNF-tumor necrosis factor-α; IL-6 and IL-10—interleukins 6 and 10; WBC—white blood cells.